Category: 40180-04-9

Matsunaga, Norikazu published the artcileAnalysis of the metabolic pathway of bosentan and of the cytotoxicity of bosentan metabolites based on a quantitative modeling of metabolism and transport in sandwich-cultured human hepatocytes, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is bosentan cytotoxicity metabolism transport hepatocyte.

To quant. understand the events in the human liver, we modeled a hepatic disposition of bosentan and its three known metabolites (Ro 48-5033, Ro 47-8634, and Ro 64-1056) in sandwich cultured human hepatocytes based on the known metabolic pathway. In addition, the hepatotoxicity of Ro 47-8634 and Ro 64-1056 was investigated because bosentan is well known as a hepatotoxic drug. A model illustrating the hepatic disposition of bosentan and its three metabolites suggested the presence of a novel metabolic pathway(s) from the three metabolites. By performing in vitro metabolism studies on human liver microsomes, a novel metabolite (M4) was identified in Ro 47-8634 metabolism, and its structure was determined Moreover, by incorporating the metabolic pathway of Ro 47-8634 to M4 into the model, the hepatic disposition of bosentan and its three metabolites was successfully estimated In hepatocyte toxicity studies, the cell viability of human hepatocytes decreased after exposure to Ro 47-8634, and the observed hepatotoxicity was diminished by pretreatment with tienilic acid (CYP2C9-specific inactivator). Pretreatment with 1-aminobenzotriazole (broad cytochrome P 450 inactivator) also tended to maintain the cell viability. Furthermore, Ro 64-1056 showed hepatotoxicity in a concentration dependent manner. These results suggest that Ro 64-1056 is directly involved in bosentan-induced liver injury partly because CYP2C9 specifically mediates hydroxylation of the t-Bu group of Ro 47-8634. Our findings demonstrate the usefulness of a quant. modeling of hepatic disposition of drugs and metabolites in sandwich cultured hepatocytes. In addition, the newly identified metabolic pathway may be an alternative route that can avoid Ro 64-1056- induced liver injury.

Drug Metabolism & Disposition published new progress about Anxiety disorders. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Name: 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

David, C. published the artcileSubstrate specificity of the luminal sodium-dependent sulfate transport system in the proximal renal tubule as compared to the contraluminal sulfate exchange system, COA of Formula: C13H8Cl2O4S, the main research area is sulfate transporter specificity kidney proximal tubule.

The efflux of [35S]sulfate from the lumen of the proximal renal tubule into tubular cells of rats was measured by the stop-flow tubular-lumen microperfusion technique. The transport parameters obtained and the apparent Ki values of competing substrates were compared with those of the contraluminal influx of [35S]-sulfate from the interstitium into tubular cells. For the luminal (l) sulfate efflux a Km(l, SO42-) of 0.8 mmol/L and a Jmax(l, SO42-) of 0.2 pmol s-1 cm-1 were found. The corresponding contraluminal (cl) values were Km(cl,SO42-) 2.5 mmol/L and Jmax(cl,SO42-) 1.2 pmol s-1 cm-1. Omission of Na+ from the perfusates reduced the luminal efflux of sulfate by 83%, while the contraluminal influx of sulfate was not changed. The most effective inhibitors of both sulfate transport systems are 8-anilino-1-naphthalenesulfonate, orange G, and H2-DIDS. The data indicate that the Na+-dependent luminal and the Na+-independent contraluminal sulfate transport systems accommodate a similar spectrum of anionic substrates, whereby the inhibitory potency against the luminal Na+-dependent sulfate transport system is identical or smaller than against the contraluminal transporter.

Pfluegers Archiv published new progress about Biological efflux. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, COA of Formula: C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Rudik, A. V. published the artcilePrediction of metabolites of epoxidation reaction in MetaToxdol, Application of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, the main research area is xenobiotics epoxide metabolite epoxidation reaction MetaTox; AUC, area under the ROC curve; Epoxidation; IAP, invariant accuracy of prediction; LMNA, labelled multilevel neighbourhoods of atom; LOO CV, leave-one-out cross-validation; MNA, multilevel neighbourhoods of atom; PASS; SOE, acute toxicity; SOM, site of metabolism; SoLA, structure with one labelled atom; biotransformation; metabolism; prediction; prediction of activity spectra for substances; reactive metabolite; tienilic acid; toxic metabolite; xenobiotics metabolism.

Biotransformation is a process of the chem. modifications which may lead to the reactive metabolites, in particular the epoxides. Epoxide reactive metabolites may cause the toxic effects. The prediction of such metabolites is important for drug development and ecotoxicol. studies. Epoxides are formed by some oxidation reactions, usually catalyzed by cytochromes P 450, and represent a large class of three-membered cyclic ethers. Identification of mols., which may be epoxidized, and indication of the specific location of epoxide functional group (which is called SOE – site of epoxidation) are important for prediction of epoxide metabolites. Datasets from 355 mols. and 615 reactions were created for training and validation. The prediction of SOE is based on a combination of LMNA (Labeled Multilevel Neighborhood of Atom) descriptors and Bayesian-like algorithm implemented in PASS software and MetaTox web-service. The average invariant accuracy of prediction (AUC) calculated in leave-one-out and 20-fold cross-validation procedures is 0.9. Prediction of epoxide formation based on the created SAR model is included as the component of MetaTox web-service (http://www.way2drug.com/mg)..

SAR and QSAR in Environmental Research published new progress about Biotransformation. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Application of 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Preusch, Peter C. published the artcileMechanism of ticrynafen potentiation of coumarin anticoagulant action, HPLC of Formula: 40180-04-9, the main research area is coumarin anticoagulant ticrynafen interaction.

Ticrynafen (I) [40180-04-9] enhanced the degree of hypoprothrombinemia and altered plasma and hepatic vitamin K epoxide  [25486-55-9] concentrations in warfarin (II) [81-81-2]-treated rats. Ticrynafen did not affect vitamin K-dependent carboxylase  [81181-72-8] or vitamin K epoxide reductase  [55963-40-1] activities in vitro. Cytosolic DT-diaphorase  [9032-20-6] was very sensitive to ticrynafen inhibition in vitro, and inhibition of vitamin K  [12001-79-5] reduction via this enzyme is a possible mechanism by which ticrynafen potentiates coumarin anticoagulant action. Inhibition of this enzyme may also contribute to the reported hepatotoxicity of ticrynafen.

Biochemical Pharmacology published new progress about Blood coagulation. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, HPLC of Formula: 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Weber, Jane E. published the artcileIdentification and characterisation of new inhibitors for the human hematopoietic prostaglandin D2 synthase, SDS of cas: 40180-04-9, the main research area is crystal structure inhibitor human hematopoietic prostaglandin D2 synthase.

Prostaglandin D2 synthesized by the hematopoietic prostaglandin D2 synthase has a pro-inflammatory effect in allergic asthma, regulating many hallmark characteristics of the disease. Here we describe identification of hematopoietic prostaglandin D2 synthase inhibitors including cibacron blue, bromosulfophthalein and ethacrynic acid. Expansion around the drug-like ethacrynic acid identified a novel inhibitor, nocodazole, and a fragment representing its aromatic core. Nocodazole binding was further characterized by docking calculations in combination with conformational strain anal. The benzyl thiophene core was predicted to be buried in the active site, binding in the putative prostaglandin binding site, and a likely hydrogen bond donor site identified. X-ray crystallog. studies supported the predicted binding mode.

European Journal of Medicinal Chemistry published new progress about Crystal structure. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, SDS of cas: 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Yasuo, Kazuya published the artcileStructure-Based CoMFA As a Predictive Model – CYP2C9 Inhibitors As a Test Case, Application In Synthesis of 40180-04-9, the main research area is structure CoMFA CYP2C9 inhibitor.

In this study, we tried to establish a general scheme to create a model that could predict the affinity of small compounds to their target proteins. This scheme consists of a search for ligand-binding sites on a protein, a generation of bound conformations (poses) of ligands in each of the sites by docking, identifications of the correct poses of each ligand by consensus scoring and MM-PBSA anal., and a construction of a CoMFA model with the obtained poses to predict the affinity of the ligands. By using a crystal structure of CYP 2C9 and the twenty known CYP inhibitors as a test case, we obtained a CoMFA model with a good statistics, which suggested that the classification of the binding sites as well as the predicted bound poses of the ligands should be reasonable enough. The scheme described here would give a method to predict the affinity of small compounds with a reasonable accuracy, which is expected to heighten the value of computational chem. in the drug design process.

Journal of Chemical Information and Modeling published new progress about Crystal structure. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Application In Synthesis of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

O’Reilly, Robert A. published the artcileTicrynafen-racemic warfarin interaction: hepatotoxic or stereoselective?, Product Details of C13H8Cl2O4S, the main research area is ticrynafen warfarin interaction stereoselective.

Normal subjects received large single doses of 1.5 mg/kg racemic warfarin (racemic I) [81-81-2] with and without daily oral doses of 250 mg ticrynafen (II) [40180-04-9] beginning 3 days before I and continuing for the duration of hypoprothrombinemia. II induced augmentations of both prothrombin time and plasma I concentration The interaction was evaluated further with separated I enantiomorphs. II induced augmentation of prothrombin times and I concentrations of S-I  [5543-57-7], but had little effect on R-I  [5543-58-8]. Thus, II probably augments the hypoprothrombinemia of racemic I by reducing metabolic clearance of S-I. The lack of effect of II on R-I suggests that the interaction is stereoselective rather than hepatotoxic.

Clinical Pharmacology & Therapeutics (St. Louis, MO, United States) published new progress about Drug interactions. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Product Details of C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Schlatter, E. published the artcileEffect of “”high ceiling”” diuretics on active salt transport in the cortical thick ascending limb of Henle’s loop of rabbit kidney. Correlation of chemical structure and inhibitory potency, Category: benzothiophene, the main research area is diuretic structure kidney salt transport.

The effects of “”high ceiling”” diuretics on the thick ascending limb of the loop of Henle (TAL) and the effect of structure modification on the inhibitory effect of furosemide (I) [54-31-9] on the Na+-2Cl–K+ cotransport system present in the lumen membrane of the TAL were investigated. Isolated cortical TAL (cTAL) segments of rabbit kidneys were perfused in vitro. The equivalent short-circuit current, as a measure of active salt transport, was correlated to the concentration of 64 substances. The results indicated that the so-called “”high ceiling”” or “”loop”” diuretics consist of at least 3 groups: drugs that do not interfere with the active salt transport in the cTAL segment, drugs that interfere by as-yet-uncharacterized mechanisms, and drugs of the furosemide type which inhibit the Na+-2Cl–K+ cotransport system in the lumen membrane of the cTAL segment.

Pfluegers Archiv published new progress about Biological transport. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Category: benzothiophene.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Ullrich, Karl J. published the artcileLuminal transport step of para-aminohippurate (PAH). Transport from PAH-loaded proximal tubular cells into the tubular lumen of the rat kidney in vivo, COA of Formula: C13H8Cl2O4S, the main research area is luminal transport aminohippurate rat kidney; benzoate transport inhibition aminohippurate lumen kidney; uricosuric compound transport inhibition aminohippurate kidney.

Proximal tubular cells were loaded for 10 s with [3H]para-aminohippurate ([3H]PAH) by microperfusing the peritubular capillaries with Ringer solution containing 0.05 mmol/l PAH. Immediately thereafter [3H]PAH influx from cells into a column of equilibrium solution injected into the oil-filled tubular lumen was measured by re-aspirating the fluid after 1-10 s of contact time. The rise of luminal PAH concentration within 2 s of contact time was almost linear, reaching a luminal / capillary concentration ratio of 1.6 after 2 s and of 3.2 after 5 s. The 2-s PAH concentration ratio was not changed when different maneuvers were applied to depolarize proximal tubular cells. Also, the 2-s PAH concentration ratio was not influenced by varying the luminal pH from 6.0 to 8.0 or the luminal Cl- concentration from zero to 134 mmol/l or when either 5 mmol/l urate or 25 mmol/l lactate was in the luminal perfusate. A decrease in the 2-s PAH concentration ratio, i.e. trans-inhibition, was observed when 25 or 50 mmol/l HCO3-(-50%) was in the luminal perfusate. Trans-inhibition was also seen with 5 mmol/l of the following substituted benzoates: 2-hydroxybenzoate (-58%), 2-methoxybenzoate (-46%), 2-hydroxybenzoate acetyl ester (-36%), 2-hydroxy-3,5-dinitrobenzoate (-48%), 3,5-dichlorobenzoate (-49%), and 2,3,5-trichlorobenzoate (-45%). No effect was seen with benzoate, 3-hydroxybenzoate, 2-chlorobenzoate, 2-nitrobenzoate, 2,5-dinitrobenzoate, 3-sulfamoylbenzoate and 4-sulfamoylbenzoate. However, analogs of the latter 2 compounds possessing 2 addnl. side groups, such as furosemide and piretanide, or a hydrophobic moiety, such as probenecid, were inhibitory (by -62, -41 and -49% resp.). Phenoxyacetate had no effect; however, it inhibited if in addition it had 3 chloro groups, as in 2,4,5-trichlorophenoxyacetate (-71%) or a hydrophobic carbamoyl side group, as in mersalylic acid (salyrgan, -75%). Benzene-sulfonate trans-inhibited (-33%), as did phenolsulfonphthalein (phenol red, -39%) and sulfofluorescein (-55%). However, the trans-inhibitory effect of the corresponding carboxy compounds was absent (phenolphthalein) or weaker (fluorescein, -42%). The trans-inhibitory effect of the uricosurics ethacrynic acid (-53%), tienilic acid (-55%) indacrinone (-72%) and benzbromarone (-42%) could be attributed to 2 chloro or bromo side groups on the benzene ring. Other trans-inhibiting uricosuric substances were indomethacin (-42%), sulfinpyrazone (-38%), losartan (-80%) its metabolite EXP 3174 (-55%), and AA 193 (-65%). These organic acids, with pKa values between 2.8 and 4.9, possess chloro and sulfin groups, as well as heterocyclic 5-ring and hydrophobic ring or chain areas. No significant effect was seen with 5 mmol/l PAH, 2-oxo-glutarate, DIDS, cGMP, prostaglandin E2, cortisol, benzylamiloride, pyrazinoic acid, and 25 mmol/l lactate. Our data indicate that in situ the secretory luminal PAH transport proceeds in a nonrheogenic fashion, per exclusionem by anion exchange. The observed trans-inhibition of PAH secretion seems to correlate with the affinity for the luminal PAH transporter and, for uricosuric substances, with their uricosuric potency.

Pfluegers Archiv published new progress about Biological transport. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, COA of Formula: C13H8Cl2O4S.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem

Milton, A. published the artcileRenal tubular accumulation of organic substances: a new in vivo method which differentiates between luminal and peritubular uptake, Computed Properties of 40180-04-9, the main research area is kidney tubule uptake organic compound; radioassay kidney uptake organic compound.

By using a modification of the Sperber technique, cellular uptake of organic substances in the kidney was studied. A test substance was mixed with an extracellular marker (EDTA or inulin), both radiolabeled with an activity ratio close to 1 and injected into the renal portal system on 1 side via a leg vein. The animals were killed 1-10 min after injection and the radioactivity in different organs determined There were significantly higher ipsilateral (injection) to contralateral (control) kidney ratios (substance to marker) at 1 min after injection for Na o-[125I]iodohippurate (125I-Hipp), [14C]tetraethylammonium bromide (14C-TEA), [3H]dihydromorphine (3H-DHM), and [125I]iothalamate, with a progressive decrease in injection kidney ratios for 125I-Hipp and 14C-TEA when death occurred after a longer period. Inhibition of renal tubular transport with novobiocin or mepiperphenidol markedly reduced 1- and 4-min injection kidney ratios for 125I-Hipp and 14C-TEA, resp. When death occurred after a longer period, ratios in both kidneys increased significantly for [125I]iothalamate. A good correlation was found between peak cellular accumulation in the kidney and excretion efficiency of test substances. Thus, the results indicate (1) that 125I-Hipp, [125I]iothalamate, 14C-TEA, and 3H-DHM were accumulated from the peritubular side of the nephron through the transport systems for organic acids and bases, resp., and (2) that [125I]iothalamate also showed luminal uptake. This new in vivo technique is simple and well suited for studying renal tubular accumulation of organic substances and offers the advantage of being able to distinguish luminal from peritubular uptake.

Acta Physiologica Scandinavica published new progress about Biological transport. 40180-04-9 belongs to class benzothiophene, name is 2-(2,3-Dichloro-4-(thiophene-2-carbonyl)phenoxy)acetic acid, and the molecular formula is C13H8Cl2O4S, Computed Properties of 40180-04-9.

Referemce:
Benzothiophene – Wikipedia,
Benzothiophene | C8H6S – PubChem